The physiological and clinical significance of endogenous analgesic mechanisms within the brainstem has led to intense efforts to characterize the anatomy and physiology of specific cell groups within the ventral medulla. However, while medullary-spinal efferents have been described, the actual neural areas involved in descending inhibitory mechanisms have yet to be determined. Currently considerable controversy remains over the delineation of nucleus raphe magnus (NRM) as a medullary structure critical to sensory modulation. Indeed, the ventral medulla adjacent to NRM has also been implicated in nociception, receiving major efferents from periaqueductal grey (PAG) and contributing to pathways which terminate within the dorsal and ventral horn as well as the intermediolateral cell column. Many recent studies have concentrated on projections from the ventral medulla which descend in the dorsolateral funiculus but not much attention has been paid to ascending connections from this region. The amygdala of the limbic forebrain is a major target of endogenous opiates, has been implicated in nociception, and has been shown to provide an excitatory projection to PAG; however, there is little information regarding pathways by which the structure receives nociceptive related information. Preliminary data from our laboratory indicates that NRM and nucleus paragigantocellularis lateralis (PGCL) send direct projections to amygdala, whereas projections from nucleus paragigantocellularis (PGC) are sparse or non-existent. Thus, there may be a brainstem pathway for the transmission of nociceptive related information to the limbic system. Such ascending pathways are expected to provide a promising avenue for delineating the organization of the ventral medulla and may lead to a more comprehensive understanding of the neural substrates of nociception. We propose to investigate these questions in more detail using retrograde and anterograde pathway tracing methods, immunohistochemistry and intracellular physiological recording with HRP labeling to map out various ascending and descending projections of NRM, PGC, and PGCL. The specific aims are to: (1) Further characterize the relationship between NRM, PGC and PGCL and their projections to amygdala and spinal cord. (2) Determine whether specific cells in NRM, PGC and PGCL projecting to amygdala or spinal cord receive terminals from sources known to play a role in sensory transmission or anti-nociception. (3) Determine if differences in anatomical organization are correlated with differences in physiological responsiveness.